Good Antileishmanial Activity Research Articles

Averrhoa carambola Leaf Extract Induces Apoptosis-Like Death with Increased ROS Generation in Leishmania donovani.

The parasitic disease leishmaniasis is responsible for high mortality and morbidity rates worldwide. The visceral form is the most severe form of leishmaniasis (or leishmaniosis), which is caused predominantly by Leishmania donovani. Currently, clinically recommended antileishmanial drugs are not convenient because of several medical complications and resistance issues. Phytocompounds are the best candidates in this regard. The present study aimed to evaluate the antileishmanial activity of Averrhoa carambola leaf extract. The antipromastigote activity and cytotoxicity were assessed using the MTT assay. Morphological distortions were determined using phase contrast microscopy and scanning electron microscopy (SEM). Reactive oxygen species (ROS) production, nonprotein thiol depletion and apoptotic death in promastigotes were determined via flow cytometry. UV-visible spectroscopy and energy dispersive X-ray (EDX) spectroscopy was performed for elemental analysis. Fourier-transform infrared spectroscopy (FTIR) and liquid chromatography‒mass spectrometry (LCMS) were used to characterize the phytocomponent(s) present in the extract. The chloroform extract of Averrhoa carambola leaf (ACCEX) (IC50 = 50.76 ± 1.7µg/mL) exhibited the highest activity, followed by the ethyl acetate, hexane, and methanol extracts. ACCEX has also exhibited lower toxicity towards host macrophages. ACCEX also induced morphological distortions in promastigotes, with significant generation of ROS and the concomitant apoptosis initiation followed by a decrease in the nonprotein thiol level. The major phytometabolites present in ACCEX were identified from the National Institute of Standards and Technology (NIST) database and from a literature review. This study suggested that Averrhoa carambola leaf extracts are rich in some classes of biologically active phytocompounds and exhibit good antileishmanial activity.

Synthesis of Nitrostyrylthiazolidine-2,4-dione Derivatives Displaying Antileishmanial Potential.

A series of 61 thiazolidine-2,4-diones bearing a styryl group at position 5 was synthesized in 2-5 steps and their structure was proved by elemental and spectral analyses. The compounds obtained were evaluated in vitro against the promastigote stage of the kinetoplastid parasite Leishmania infantum and the human HepG2 cell line, to determine selectivity indices and to compare their activities with those of antileishmanial reference drugs. The study of structure-activity relationships indicated the potential of some derivatives bearing a nitro group on the phenyl ring, especially when located at the meta position. Thus, among the tested series, compound 14c appeared as a hit compound with good antileishmanial activity (EC50 = 7 µM) and low cytotoxicity against both the hepatic HepG2 and macrophage THP-1 human cell lines (CC50 = 101 and 121 µM, respectively), leading to good selectivity indices (respectively, 14 and 17), in comparison with the reference antileishmanial drug compound miltefosine (EC50 = 3.3 µM, CC50 = 85 and 30 µM, SI = 26 and 9). Regarding its mechanism of action, among several possibilities, it was demonstrated that compound 14c is a prodrug bioactivated, predominantly by L. donovani nitroreductase 1, likely leading to the formation of cytotoxic metabolites that form covalent adducts in the parasite. Finally, compound 14c is lipophilic (measured CHI LogD7.7 = 2.85) but remains soluble in water (measured PBS solubility at pH7.4 = 16 µM), highlighting the antileishmanial potential of the nitrostyrylthiazolidine-2,4-dione scaffold.

Synthesis, characterization, exploration of anti-cancer, anti-leishmanial, anti-microbial activities, pharmacokinetic and docking studies of Sn(IV) complexes

Six new triorganotin(IV) derivatives: [(C6H5)3Sn(C11H11N2O6)] (1), [(C6H11)3Sn(C11H11N2O6)] (2), [(C7H7)3Sn(C11H11N2O6)] (3), [(CH3)3Sn(C11H11N2O6)(C10H8N2)] (4), [(CH3)3Sn(C11H11N2O6)(C12H8N2)] (5), [(CH3)3Sn(C11H11N2O6)(C14H12N4)] (6) were designed and prepared by the reaction of sodium 3‐[(4‐methoxy‐2‐nitrophenyl)carbamoyl]propanoic acid with the corresponding triorganotin(IV) chlorides. Their synthesis was confirmed by 1H, 13C and 119Sn-NMR, percentage elemental constituents, FT-IR, and ESI-mass spectrometric techniques. The OH stretching vibration of the carboxylic moiety in the spectrum of the free acid was absent in that of the sodium salt (NaL) of the acid which proves its formation. Moreover, the appearance of Sn-C and Sn-O stretching vibrations in the spectra of complexes conform their formation. The antimicrobial activity of the investigated compounds explored good antimicrobial activity in comparison to the reference drugs. The tested compounds were also treated against H-157 and BHK-21 cancerous cell lines and possess good anticancer potential in comparison to the vincristine drug used as standard. So based on the activity results it is concluded that the synthesized complexes after positive in vivo and other clinical studies may be used for cancer treatment. The tested compounds exhibit good anti-leishmanial activity. The results of molecular docking performed against cancer death receptor BRCA2 (PDB# 1NOW) and Leishmania major Pteridine reductase 1 (PTR1) of Escherichia coli BL21 (PDB # 5L42) also verify the in vitro experimental results. Pharmacokinetic properties of the tested compounds such as drug-likeness, bioavailability score etc. were determined and most of them follow the Lipinski’s rule of 5.

Synthesis, computational study, and antileishmanial and antifungal evaluation of phenoxyacetophenone hydrazones bearing a 4-arylthiazole moiety

A series of new phenoxyacetophenone hydrazones 6a-l bearing a 4-arylthiazole moiety were synthesized and tested as antileishmanial agents. After spectroscopic and computational characterization of the synthesized compounds, their antileishmanial and antifungal activities were investigated in vitro. All compounds exhibited good antileishmanial activity, demonstrating IC50 values = 3.63–17.4 μg/ml against promastigotes of Leishmania major. Certainly, the para-tolyl analog 6b showed the most potent activity against promastigotes. Compounds 6b, 6c, 6f, and 6i-6k with good activity against promastigotes (IC50 values ≤ 7.59 μg/ml) were subjected to further bioassay on the amastigotes of L. major, as well as cytotoxicity evaluation against host-cell macrophages. The representative compounds displayed substantial anti-amastigote activity (IC50 values ≤ 21.3 μg/ml) with good selectivity index (SI > 18). Additionally, the in vitro antifungal screening against yeasts, molds and dermatophytic fungi revealed that several compounds had respectable activity against dermatophytes. These results demonstrate that the thiazolyl-hydrazones 6 are proper leads for further design and development of potential antileishmanial agents.

Synthesis and evaluation of hybrid sulfonamide-chalcones with potential antileishmanial activity.

Leishmaniasis is an emerging tropical infectious disease caused by a protozoan parasite of the genus Leishmania. In this work, the molecular hybridization between a trimethoxy chalcone and a sulfonamide group was used to generate a series of sulfonamide-chalcones. A series of eight sulfonamide-chalcone hybrids were made with good yields (up to 95%). These sulfonamide-chalcones were tested against promastigotes of Leishmania amazonensis and cytotoxicity against mouse macrophages, which showed good antileishmanial activity with IC50 = 1.72-3.19 µM. Three of them (10c, 10g, and 10h) were also highly active against intracellular amastigotes and had a good selectivity index (SI > 9). Thus, those three compounds were docked in the cytosolic tryparedoxin peroxidase (cTXNPx) enzyme of the parasite, and molecular dynamics simulations were carried out. This enzyme was selected as a target protein for the sulfonamide-chalcones due to the fact of the anterior report, which identified a strong and stable interaction between the chalcone NAT22 (6) and the cTXNPx. In addition, a prediction of the drug-likeness, and the pharmacokinetic profile of all compounds were made, demonstrating a good profile of those chalcones.

Membrane-acting biomimetic peptoids against visceral leishmaniasis.

Visceral leishmaniasis (VL) is among the most neglected tropical diseases in the world. Drug cell permeability is essential for killing the intracellular residing parasites responsible for VL, making cell-permeating peptides a logical choice to address VL. Unfortunately, the limited biological stability of peptides restricts their usage. Sequence-specific oligo-N-substituted glycines ('peptoids') are a class of peptide mimics that offers an excellent alternative to peptides in terms of ease of synthesis and good biostability. We tested peptoids against the parasite Leishmania donovani in both forms, that is, intracellular amastigotes and promastigotes. N-alkyl hydrophobic chain addition (lipidation) and bromination of oligopeptoids yielded compounds with good antileishmanial activity against both forms, showing the promise of these antiparasitic peptoids as potential drug candidates to treat VL.

ACW-02 an Acridine Triazolidine Derivative Presents Antileishmanial Activity Mediated by DNA Interaction and Immunomodulation.

The present study proposed the synthesis of a novel acridine derivative not yet described in the literature, chemical characterization by NMR, MS, and IR, followed by investigations of its antileishmanial potential. In vitro assays were performed to assess its antileishmanial activity against L. amazonensis strains and cytotoxicity against macrophages through MTT assay and annexin V-FITC/PI, and the ability to perform an immunomodulatory action using CBA. To investigate possible molecular targets, its interaction with DNA in vitro and in silico targets were evaluated. As results, the compound showed good antileishmanial activity, with IC50 of 6.57 (amastigotes) and 94.97 (promastigotes) µg mL-1, associated with non-cytotoxicity to macrophages (CC50 > 256.00 µg mL-1). When assessed by flow cytometry, 99.8% of macrophages remained viable. The compound induced an antileishmanial effect in infected macrophages and altered TNF-α, IL-10 and IL-6 expression, suggesting a slight immunomodulatory activity. DNA assay showed an interaction with the minor grooves due to the hyperchromic effect of 47.53% and Kb 1.17 × 106 M-1, and was sustained by docking studies. Molecular dynamics simulations and MM-PBSA calculations propose cysteine protease B as a possible target. Therefore, this study demonstrates that the new compound is a promising molecule and contributes as a model for future works.

Integrated computational and experimental approach for novel anti-leishmanial molecules by targeting Dephospho-coenzyme A kinase

Coenzyme A acts as a necessary cofactor for many enzymes and is a part of many biochemical processes. One of the critical enzymes involved in Coenzyme A synthesis is Dephospho-coenzyme A-kinase (DPCK). In this study, we have used integrated computational and experimental approaches for promising inhibitors of DPCK using the natural products available in the ZINC database for anti-leishmanial drug development. The top hit compounds chosen after molecular docking were Veratramine, Azulene, Hupehenine, and Hederagenin. The free binding energy of Veratramine, Azulene, Hupehenine, and Hederagenin was estimated. Besides the favourable binding point, the ligands also showed good hydrogen bonding and other interactions with key residues of the enzyme's active site. The natural compounds were also experimentally investigated for their effect on the L. donovani promastigotes and murine macrophage (J774A.1). A good antileishmanial activity by the compounds on the promastigotes was observed as estimated by the MTT assay. The in-vitro experiments revealed that Hupehenine (IC50 = 7.34 ± 0.37 μM) and Veratramine (IC50 = 12.46 ± 2.28 μM) exhibited better inhibition than Hederagenin (IC50 = 23.36 ± 0.54 μM) and Azulene (IC50 = 24.42 ± 3.28 μM). This work has identified novel anti-leishmanial molecules possibly acting through the inhibition of DPCK.

Chemical constituents of Mussaenda erythrophylla Schumach. & Thonn. (Rubiaceae) and their chemophenetic significance

The chemical investigation of the CH2Cl2/MeOH (1:1) extract from the aerial part of Mussaenda erythrophylla Schumach. & Thonn. (Rubiaceae) resulted in the isolation of sixteen known compounds (1–16) distributed in coumarins, flavonoid glucosides, quinic acid derivatives, triterpenoids, monoglycerid, steroids, tetraterpenoid and polyol. The structures of the compounds were determined by spectrometric and spectroscopic analysis including MS and NMR data followed by their comparison with reported ones in the literature. The chemophenetic significance of the isolated compounds was discussed. The crude extract and some of the isolated compounds were assessed in vitro for their antileishmanial, cytotoxic and antiplasmodial activities. The crude extract of M. erythrophylla showed moderate antileishmanial activity (IC50 = 61.6 μg/mL) while the hexane soluble fraction showed good antileishmanial activity (IC50 = 31.06 μg/mL) compared to the reference drug amphotericin B (IC50 = 0.11 μM). Compounds 11 and 9 also exhibited potent antileishmanial activity (IC50 = 53.7–52.0 μM). The crude extract as well as the ethyl acetate soluble fraction also exhibited good antiplasmodial activity (IC50 = 7.43 ± 0.00 μg/mL and 14.49 ± 2.96 μg/mL respectively), while compounds 11, 15 and 16 showed weak activity with IC50 > 20 μM compared to the reference drug artemisinin (IC50 = 0.014 ± 0.001 μM).

Synthesis and Biological Evaluation of Tetrahydropyrimidine and Dihydropyridine Derivatives Against Leishmania Major.

A number of tetrahydropyrimidines and their bioisosteric dihydropyridines bearing chloro substituent at various positions of phenyl ring in C4 of main scaffolds were designed, synthesized and evaluated for antileishmanial activity. The antileishmanial activity of the synthesized compounds was evaluated against promastigote and amastigote forms. Moreover, molecular docking studies of the compounds in pteridine reductase 1 (PTR1) pocket were carried out to describe the results of biological experiments. The compounds exhibited moderate to good antileishmanial activity against promastigote and amastigote forms. Among the screened compounds, 1d and 2c were found as the most potent compounds against promastigote form with EC50 values of 15.5 and 10.5µM, respectively. Compounds 2a and 2c were the most potent compounds against amastigote form with EC50 values of 5.4 and 2.2µM, respectively. According to structure-activity relationship (SAR) studies, the chloro substituent in different positions of phenyl ring at C4 of 1,2,3,4-tetrahydropyrimidine (THPM) and 1,4-dihydropyridine (DHP) rings and also the length of the chain belonging to the ester groups could be important for antileishmanial activity of these compounds. Most of these compounds exhibited low cytotoxicity against macrophages. Compounds 1h, 2a, 2b and 2c revealed higher activity than glucantime while all compounds showed lower activity toward amphotericine B. Docking studies showed that the synthesized compounds were fit well in the PTR1 pocket. Compounds 1h and 2c indicated the highest score docking among screened compounds in PTR1 enzyme.

Antitrypanosomal and Antileishmanial Activity of Chalcones and Flavanones from Polygonum salicifolium.

Trypanosomiasis and leishmaniasis are a group of neglected parasitic diseases caused by several species of parasites belonging to the family Trypansomatida. The present study investigated the antitrypanosomal and antileishmanial activity of chalcones and flavanones from Polygonum salicifolium, which grows in the wetlands of Iraq. The phytochemical evaluation of the plant yielded two chalcones, 2′,4′-dimethoxy-6′-hydroxychalcone and 2′,5′-dimethoxy-4′,6′-dihydroxychalcone, and two flavanones, 5,7-dimethoxyflavanone and 5,8-dimethoxy-7-hydroxyflavanone. The chalcones showed a good antitrypanosomal and antileishmanial activity while the flavanones were inactive. The EC50 values for 2′,4′-dimethoxy-6′-hydroxychalcone against Trypanosoma brucei brucei (0.5 μg/mL), T. congolense (2.5 μg/mL), and Leishmania mexicana (5.2 μg/mL) indicated it was the most active of the compounds. None of the compounds displayed any toxicity against a human cell line, even at 100 µg/mL, or cross-resistance with first line clinical trypanocides, such as diamidines and melaminophenyl arsenicals. Taken together, our study provides significant data in relation to the activity of chalcones and flavanones from P. salicifolium against both parasites in vitro. Further future research is suggested in order to investigate the mode of action of the extracted chalcones against the parasites.

Antiprotozoal Activity of Xanthone Derivatives

A series of xanthone derivatives containing different side chains, including ω-bromo and ω-aminoalkoxylxanthones (with linear alkoxy chains of 3, 4 and 5 carbon atoms and methyl, propyl, tert -butylamino and piperidinyl moieties), synthesized from the natural xanthone lichexanthone were tested for their antiprotozoal activities against Leishamania braziliensis , L. major and Trypanosoma cruzi (extra and intracellular forms). The ω-aminoalkoxylxanthones showed good antileishmanial activity, with IC 50 ranging from 62.8 to 0.1 µM for promastigotes and 119.3 to 2.4 µM for amastigotes. In general, compounds with longer alkyl chains and tert -butylamino moiety showed better activity. The cytotoxicity on VERO cells was also described for some derivatives. Compound 15 ( tert -butylaminobutyloxy side chain) was the most active on promastigote forms (IC 50 0.1 µM), compound 16 ( tert -butylaminopentyloxy side chain) sowed the best activity for amastigotes (IC 50 2.4 µM) and derivative 13 (dipropylaminopentyloxy side chain) was the most selective (selectivity index of 9.4). Regarding trypanocidal activity, 16 and other groups of derivatives, (ω-bromoalkoxylxanthones, prenyl and epoxyl side chains) had moderate to good activity on T. cruzi trypomastigotes, with IC 50 ranging from 30.6 to 4.1 µM, while only two ω-aminoalkoxylxanthones ( 10 and 11 ) were weakly active against T. cruzi amastigotes. DOI: http://dx.doi.org/10.17807/orbital.v12i3.1460

Efficacy of photodynamic therapy using TiO2 nanoparticles doped with Zn and hypericin in the treatment of cutaneous Leishmaniasis caused by Leishmania amazonensis.

Since Leishmania parasites exhibit resistance outbreaks to drugs conventionally used in medical treatments, research of new antileishmanial compounds or alternative treatment therapies are essential. A focus of interest has been the implementation of light-based therapies such as photodynamic therapy, where inorganic compounds such as titanium dioxide have shown promising results as drug delivery carriers. In this work, nanoparticles of TiO2 doped with Zn (TiO2/Zn) were synthesized through solution combustion route and with hypericin (HY) in order to enhance its photodynamic activity in the visible light region. Scanning (SEM) and transmission (TEM) electron microscopy analyses showed particles of (TiO2/Zn) with sizes smaller than 20 nm and formation of aggregates smaller than 1 μm, whilst electron diffraction spectroscopy (EDS) analysis ensured the presence of Zn in the system. The association of the TiO2/Zn with HY (TiO2/Zn-HY) was further confirmed by fluorescence spectrometry. Measurements of its cellular uptake showed the presence of smaller molecules into promastigotes after 120 min incubation. TiO2/Zn-HY showed good antileishmanial activity (EC50 of 17.5 ± 0.2 μg mL-1) and low cytotoxicity against murine macrophages (CC50 35.2 ± 0.3 μg mL-1) in the visible light (22 mW cm-2; 52.8 J cm-2). Moreover, in the in vivo analysis, TiO2/Zn-HY decreased the parasite load of L. amazonensis - BALB/c infected mice by 43% - 58% after a combination of blue and red light presenting 22 mW cm-2 of intensity and 52.8 J cm-2 of fluency delivered. All together, these data indicate a new combined system of nanoparticles associated with a photosensitizer and PDT as alternative to amphotericin B for the treatment of cutaneous leishmaniasis.

Synthesis and evaluation of thiadiazole-based antileishmanial agents

Background and Objectives: The 1, 3, 4-thiadiazole scaffold is one of the principal structural components, in a variety of drug categories such as antimicrobial, anti-inflammatory, antineoplastic, and antileishmanial agents. Considering the reported antileishmanial effects of thiadiazole derivatives and the importance of this disease, some of the thiadiazole derivatives with modifications at sulfur atom or amine group attached to the 2-position were synthesized and evaluated for antileishmanial activity. Materials and Methods: Derivatives of 1,3,4-thiadiazole including 2-substituted-thio-1,3,4-thiadiazoles bearing (5-(4-nitrobenzylideneamino) or 5-amino (II, IV, V) and one derivative of 2-substituted-amino-1,3,4-thiadiazole bearing (5- (4-nitrophenyl) (VII) were synthesized and evaluated for their in vitro antileishmanial activity against promastigote and amastigote forms of the Leishmania major. Results: The most active compound was found to be compound II after 24-h incubation against promastigotes and amastigotes with the half maximal inhibitory concentration (IC50) values of 44.4 µM and 64.7 µM, respectively. Conclusion: All of the synthesized compounds showed good antileishmanial activity against both forms of L. major after 48 and 72h incubation.

Antileishmanial Potential of Propolis Essential Oil and Its Synergistic Combination With Amphotericin B

The antileishmanial activity of Tunisian propolis essential oil (EO) and its combination with amphotericin B was investigated against 2 local clinical strains of Leishmania: Leishmania major and Leishmania infantum. The cytotoxic potential of this EO was evaluated against macrophage Raw264.7. Combination of propolis EO and amphotericin B was investigated using the checkerboard method. The propolis sample was collected from the region of Beni Khalled, a Tunisian city located west of Cape Bon (Nabeul). Its location is particular since it is near to sea with a steppe climate and the predominance of citrus trees. The EO was obtained by Clevenger-type apparatus. Its chemical composition was identified using gas chromatography with flame ionization detector and gas chromatography-mass spectrometry analysis. Our results demonstrate that Tunisian propolis EO exhibit good antileishmanial activity against L. major and L. infantum promastigotes (IC50 = 5.29 ± 0.31 and 3.67 ± 0.52 µg/mL, respectively) and amastigotes (IC50 = 7.38 ± 0.45 and 4.96 ± 0.24 µg/mL, respectively). Moreover, it reduced significantly the parasite proliferation on a dose-dependent response (95%) with low cytotoxicity (selectivity index = 16.18 and 23.33, respectively). Its combination with amphotericin B showed a synergistic potential (fractional inhibitory concentration = 0.37). Interestingly, the data suggest that propolis EO was involved in macrophage activation by hyperproduction of NO. A total of 51 compounds were identified in the propolis EO. The major compound identified was α-pinene (36.7% ± 2.36%) followed by α-cedrol (6.7% ± 0.10%), totarol (6.6% ± 0.09%), and dehydroabietane (5.2% ± 0.10%). Our findings suggest that Tunisian propolis might constitute a promising source for antileishmanial molecules.

Study of Ethinyl Estradiol Activity Against Promastigotes, Axenic and Macrophage-Dwelling Amastigotes of Leishmania infantum by Using Atomic Force Microscopy and Methyl Thiazolyl Tetrazolium Methods

Background: In the era of drug resistant organisms, there exists a huge need to overcome this issue. Drug repositioning is the action of repurposing current drugs against alternative targets. Objectives: Herein, we assessed the antileishmanial activity of ethinyl estradiol and tolmetin on the promastigotes and amastigotes of Leishmania infantum, using methyl thiazolyl tetrazolium (MTT) and atomic force microscopy (AFM) methods. Methods: Following previous in silico evaluation of 3358 FDA-approved compounds, ethinyl estradiol and tolmetin drugs were selected. Promastigote assay was done in RPMI 1640 culture in 96-well plates (105/100 µL). Also, axenic amastigotes cultured in acidic RPMI 1640 were seeded in 96-well plates (5 × 104 parasites). Raw 264.7 macrophages were seeded at a density of 3 × 106 cells/well. Then, the macrophages were infected with metacyclic promastigotes of L. infantum. Also, drug solvent and amphotericin B were considered as control wells. Drug challenge was performed in triplicate with different concentrations of ethinyl estradiol (250, 125, 62.5, 31.25, 15.62 and 7.81 µg/mL) and tolmetin (200, 100, 50, 25, 12.5 and 6.25 µg/mL) and cell viability was assessed by MTT assay. AFM imaging was done to observe morphological changes. Results: The main finding of our investigation was the substantial effect of ethinyl estradiol on promastigotes, and amastigotes of L. infantum during 24, 48 and 72 h, according to MTT results and cellular morphology observations. Thus, the IC50 of this drug on promastigote, axenic amastigotes and macrophage-dwelling amastigotes during 72 h was 23, 45 and 32 µg/mL, respectively. However, tolmetin was not effective against L. infantum parasites. Cellular alteration, was observed by AFM technique. Conclusions: This study showed that ethinyl estradiol had good anti-leishmanial activity and it is recommended to test this drug under in vivo condition. With the aid of drug repurposing we could substitute the old drugs with novel compounds for a specific disease.

Identification of dehydroxy isoquine and isotebuquine as promising antileishmanial agents

Traditional antimalarial drugs based on 4-aminoquinolines have exhibited good antiproliferative activities against Leishmania parasites; however, their clinical use is currently limited. To identify new 4-aminoquinolines to combat American cutaneous leishmaniasis, we carried out a full in vitro evaluation of a series of dehydroxy isoquines and isotebuquines against two Leishmania parasites such as Leishmania braziliensis and Leishmania mexicana. First, the antiproliferative activity of the quinolines was studied against the promastigote forms of L. braziliensis and L. mexicana parasites, finding that five of them exhibited good antileishmanial responses with micromolar IC50 values ranging from 3.84 to 10 μM. A structure-activity relationship analysis gave evidence that a piperidine or a morpholine attached as N-alkyamino terminal substituent as well as the inclusion of an extra phenyl ring attached at the aniline ring of the isotebuquine core constitute important pharmacophores to generate the most active derivatives, with antileishmanial responses by far superior to those found for the reference drug, glucantime. All compounds showed a relatively low toxicity on human dermis fibroblasts, with CC50 ranging from 69 to >250 μM. The five most active compounds displayed moderate to good antileishmanial activity against the intracellular amastigote form of L. braziliensis, compared to the reference drug. In particular, compound 2j was identified as the most potent agent against antimony-resistant amastigotes of L. braziliensis with acceptable biological response and selectivity, emerging as a promising candidate for further in vivo antileishmanial evaluation. Diverse mechanism-of-action studies and molecular docking simulations were performed for the most active 4-aminoquinoline.

Antileishmanial activity of new hybrid tetrahydroquinoline and quinoline derivatives with phosphorus substituents

Heterocyclic compounds, such as hybrid tetrahydroquinoline and quinoline derivatives with phosphorated groups, have been prepared by multicomponent cycloaddition reaction between phosphorus-substituted anilines, aldehydes and styrenes. The antileishmanial activity of these compounds has been evaluated on both promastigotes and intramacrophagic amastigotes of Leishmania infantum. Good antileishmanial activity of functionalized tetrahydroquinolines 4a, 5a, 6b and quinoline 8b has been observed with similar activity than the standard drug amphotericin B and close selective index (SI between 43 and 57) towards L. infantum amastigotes to amphotericin B. Special interest shows tetrahydroquinolylphosphine sulfide 5a with an EC50 value (0.61 ± 0.18 μM) similar to the standard drug amphotericin B (0.32 ± 0.05 μM) and selective index (SI = 56.87). In addition, compound 4c shows remarkable inhibition on Leishmania topoisomerase IB. Parallel theoretical study of stereoelectronic properties, application of docking-based virtual screening methods, along with molecular electrostatic potential and predictive druggability analyses are also reported.

Crystal Engineering of Naturally Occurring Seselin To Obtain Cocrystal with Enhanced Anti-Leishmanial Activity, Hirshfeld Surface Analysis, and Computational Insight

Seselin (8,8-dimethyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-2-one) is a naturally occurring pyrano coumarin, isolated from Seseli diffusum (Roxb. ex Sm., Sant. & Wagh.). We have synthesized the cocrystal of seselin with thiourea by using liquid-assisted grinding and solution methods (via refluxing). The purity and homogeneity of the seselin/thiourea (1:1) cocrystal were confirmed by analysis based on the single-crystal X-ray diffraction technique. A deep insight into the geometry of the cocrystal demonstrated that 1:1 cocrystal stoichiometry is sustained by N–H···O hydrogen bonding between amine (−NH2) groups of thiourea and the carbonyl group of seselin. The synthesized cocrystal exhibited good anti-leishmanial activity in vitro (IC50 = 13.2 ± 1.2 μg/mL) in comparison to seselin (IC50 = 29.4 ± 1.0 μg/mL) and thiourea (IC50 = 86.06 ± 0.6 μg/mL), against the tested standards, pentamidine (IC50 = 5.09 ± 0.09 μg/mL) and amphotericin B (IC50 = 0.29 ± 0.05 μg/mL). Geometrical values of the computationally optimized...

Synthesis and antileishmanial activity of antimony (V) complexes of hydroxypyranone and hydroxypyridinone ligands.

A novel series of antimony (V) complexes with the hydroxypyranone and hydroxypyridinone ligands were synthesized and characterized by 1HNMR, FT-IR and electron spin ionization mass spectroscopic (ESI-MS) techniques. The synthesis process involved protection of hydroxyl group followed by the reaction of the intermediate with primary amines and finally deprotection. All compounds were evaluated for in vitro activities against the amastigote and promastigote forms of Leishmania major. Most of the synthesized compounds exhibited good antileishmanial activity against both forms of L. major. IC50 values of the most active compounds; 9d, 9d and 9e, after 24, 48 and 72 h against amastigote model were 15, 12.5 and 5.5 μg/mL, respectively. 9e, 11 and 9e inhibited the promastigote form of parasite after 24, 48 and 72 h with IC50 values of 10, 2 and 1 μg/mL, respectively.